Lysosomal storage disorders are a type of disease involving partial or complete deficiency of a lysosomal hydrolase. This deficiency results in incomplete lysosomal digestion of substrates specific to the hydrolase. Over time, the accumulation of undigested substrate can lead to various abnormalities, including progressive and severe neuro- and muscular-degeneration (see e.g., Settembre et al., Human Mol. Genet. 17:119-129, 2008; Fukuda et al., Curr. Neurol. Neurosci. Rep. 7:71-77, 2007). Pompe disease (a.k.a. Glycogenosis type II (GSDII)) is a type of lysosomal storage disorder caused by partial or complete deficiency of lysosomal acid α-glucosidase (GAA). The disease has been separated into two broad categories: infantile onset and late-onset. Patients with the infantile form generally die within the first year of life, due to cardiorespiratory failure. The late-onset form presents any time after infancy with generally no cardiac involvement but progressive skeletal muscle myopathy, leading to eventual respiratory failure. For a review, see Fukuda et al., Curr. Neurol. Neurosci. Rep. 7:71-77, 2007.
Enzyme replacement therapy (ERT) is used to treat several lysosomal storage disorders. In Pompe disease, ERT involves intravenous injections of a recombinant human GAA (rhGAA) precursor protein, which is internalized into cells where it rescues the GAA deficiency. ERT for Pompe disease is effective for glycogen clearance in cardiac muscle, but less effective for glycogen clearance from skeletal muscle (Raben et al., Acta Myologica 26:45-48, 2007). See also Fukuda et al., Curr. Neurol. Neurosci. Rep. 7:71-77, 2007.
Autophagy is a conserved mechanism of degradation whereby long-lived cytosolic proteins and damaged organelles (and other cytosolic content) are enveloped in double-membrane-bound vesicles called autophagosomes, which fuse with late endosomes to deliver their contents to the lysosome (Baehrecke, Nat. Rev. Mol. Cell Biol., 6:505-510, 2005). Autophagy is involved in the cellular response to starvation, cellular differentiation, cell death, aging, cancer, and neurodegenerative disorders Inhibition of autophagy is suggested for the treatment of certain cancers (Apel et al., Cancer Res. 68:1485-1494, 2008; Seglen and Gordon, Proc. Natl. Acad. Sci. U.S.A. 79: 1889-1892, 1982; Carew et al., Autophagy 3:464-467, 2007). In several diseases, most strikingly in the neurodegenerative Huntington's Disease, up-regulation of autophagy to remove toxic aggregates appears to be a promising therapy (Winslow and Rubinsztein, Biochim. Biophys. Acta. 1782:723-729, 2008).